This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of this project is to understand how interactions of the major extracellular matrix component, hyaluronan (HA) via it's principle receptor, CD44[unreadable]regulates the pathogenesis of patent ductus arteriosus (PDA), a frequent cardiovascular defect in newborns. COX-2 inhibitors effectively close the DA in near-term infants, With a rat model, we have shown that PGE2 prepares fetal DA closure by promoting NIC formation accompanied by elevated HA that serves to occlude the DA. Deletion of the PGE2 receptor (EP4) results in fatal PDA in mice, indicating that is required for NIC formation. The overarching hypothesis is that HA- CD44/COX2 pathways regulates the timing of NIC formation to promote ductus closure after birth and assurance of patency during prenatal life. To explain this balancing act, we propose two Aims. In Aim 1, we will determine how HA-CD44 interactions promote NIC formation, and assess whether HA induces NIC formation by transdifferentiation of DA endothelium into vascular SMCs. Also, we will investigate whether HA/CD44 interaction induces COX-2/PGE2 signaling required for E18 mouse DA (the active period for NIC formation). In Aim 2, we will determine whether HA signaling inhibits NIC formation by triggering a feedback loop mechanism that upregulates secretion of a vasodilatory cytokine, TNF-a. Also, we will investigate whether a HA-COX-2-HA feedback loop is required for induction of TNF-a that may prevents the formation of NIC by blocking EnMT in vivo and in vitro. These studies will characterize the dual role of HA in preterm opening and post term DA closure.